Clostridium Difficile PICO Test!!

Background

Since publication of the 2010 Infectious Diseases Society of America (IDSA)/Society for Healthcare Epidemiology of America (SHEA) Clostridium difficile infection (CDI) clinical practice guideline, there has been continued expanding interest in the epidemiology, prevention, diagnosis, and treatment of CDI. This reflects the ongoing magnitude of these infections impacting all aspects of healthcare delivery and reaching out into the community. Also new since the previous guidelines, quality of evidence and strength of recommendations was evaluated using GRADE methodology [1–4]. While there is evidence that CDI rates have declined remarkably in England and other parts of Europe since their peak before 2010, rates have plateaued at historic highs in the United States since about 2010 [5]. Recent estimates suggest the US burden of CDI is close to 500000 infections annually, although the exact magnitude of burden is highly dependent upon the type of diagnostic tests used [6]. Depending upon the degree and method of attribution, CDI is associated with 15000–30000 US deaths [6, 7] and excess acute care inpatient costs alone exceed $4.8 billion [5]. Due to this US burden of CDI, national efforts to control and prevent CDI have been put in place including incentives for public reporting of hospital rates [8] and hospital “pay for performance” [9]. It is in this context of CDI remaining a major public health problem, undermining both patient safety and the efficiency and value of healthcare delivery, that the 2010 recommendations are now revised and updated. There are no updates in the clinical definition of CDI or the clinical manifestations of CDI. The reader is referred to the 2010 guideline for the definition, background information, and clinical manifestations of CDI.

Since completion of this guideline, a new therapeutic agent and a molecular diagnostic test platform have become available for CDI. Bezlotoxumab, a monoclonal antibody directed against toxin B produced by C. difficile, has been approved as adjunctive therapy for patients who are receiving antibiotic treatment for CDI and who are at high risk for recurrence [10]. Multiplex polymerase chain reaction (PCR) platforms that detect C. difficile as part of a panel of >20 different enteric pathogens have also become available [11]. These most recent innovations and other innovations that may become available in the near future will be covered in subsequent guideline updates.

Methods

Practice Guidelines

“Clinical practice guidelines are statements that include recommendations intended to optimize patient care that are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options” [12].

Panel Composition

A panel of 14 multidisciplinary experts in the epidemiology, diagnosis, infection control, and clinical management of adult and pediatric patients with CDI was convened to develop these practice guidelines. A systematic evidence-based approach was adopted for the guideline questions and population, intervention, comparator, outcome (PICO) formulations, the selection of patient-important outcomes, as well as the literature searches and screening of the uncovered citations and articles. The rating of the quality of evidence and strength of recommendation was supported by a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodologist. In addition to members of both IDSA and SHEA, representatives from the American Society for Health-Systems Pharmacists (ASHP), the Society of Infectious Diseases Pharmacists (SIDP), and the Pediatric Infectious Diseases Society (PIDS) were included.

Literature Review and Analysis

For this 2017 guideline update, search strategies, in collaboration with the guideline panel members, were developed and built by independent health sciences librarians from National Jewish Health (Denver, Colorado). Each strategy incorporated medical subject headings and text words for “Clostridium difficile,” limited to human studies or nonindexed citations. In addition, the strategies focused on articles published in English or in any language with available English abstracts. The Ovid platform was used to search 5 electronic evidence databases: Medline, Embase, Cochrane Central Registry of Controlled Trials, Health Technology Assessment, and the Database of Abstracts of Reviews of Effects.

To supplement the electronic search, reviewers also hand-searched relevant journals, conference proceedings, reference lists from manuscripts retained from electronic searches, and regulatory agency web sites for relevant articles. Literature searches were originally implemented on 4 December 2012, updated on 3 March 2014, and further extended to 31 December 2016. The 2010 guideline used a search cutoff of 2009 and thus for this guideline, the literature review included a defined search period of 2009–2016. Separate, nondiscrete evidence libraries were created for adults and pediatrics. The result of the searching was 14479 citations being eligible at title and abstract phase of screening for the adult literature. As the 2010 guideline did not address pediatrics as part of any searching, a decision was made to reexamine the evidence landscape for pediatric-related studies that could inform the guideline. For this, the period of 1977–2016 was searched, yielding 3572 citations eligible at title and abstract phase. Those retained at the title and abstract phase of screening were then examined at the full-text phase.

Recommendations (Top Level)

These guidelines have been developed for healthcare personnel who insert intravascular catheters and for persons responsible for surveillance and control of infections in hospital, outpatient, and home healthcare settings. This report was prepared by a working group comprising members from professional organizations representing the disciplines of critical care medicine, infectious diseases, healthcare infection control, surgery, anesthesiology, interventional radiology, pulmonary medicine, pediatric medicine, and nursing. The working group was led by the Society of Critical Care Medicine (SCCM), in collaboration with the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), Surgical Infection Society (SIS), American College of Chest Physicians (ACCP), American Thoracic Society (ATS), American Society of Critical Care Anesthesiologists (ASCCA), Association for Professionals in Infection Control and Epidemiology (APIC), Infusion Nurses Society (INS), Oncology Nursing Society (ONS), American Society for Parenteral and Enteral Nutrition (ASPEN), Society of Interventional Radiology (SIR), American Academy of Pediatrics (AAP), Pediatric Infectious Diseases Society (PIDS), and the Healthcare Infection Control Practices Advisory Committee (HICPAC) of the Centers for Disease Control and Prevention (CDC) and is intended to replace the Guideline for Prevention of Intravascular Catheter-Related Infections published in 2002.

Recommendation

Epidemiology

I. How are CDI cases best defined?

Recommendation

1. To increase comparability between clinical settings, use available standardized case definitions for surveillance of (1) healthcare facility-onset (HO) CDI; (2) community-onset, healthcare facility–associated (CO-HCFA) CDI; and (3) community-associated (CA) CDI (good practice recommendation).

II. What is the minimal surveillance recommendation for institutions with limited resources?

Recommendation

1. At a minimum, conduct surveillance for HO-CDI in all inpatient healthcare facilities to detect elevated rates or outbreaks of CDI within the facility (weak recommendation, low quality of evidence).

III. What is the best way to express CDI incidence and rates?

Recommendation

1. Express the rate of HO-CDI as the number of cases per 10000 patient-days. Express the CO-HCFA prevalence rate as the number of cases per 1000 patient admissions (good practice recommendation).

IV. How should CDI surveillance be approached in settings of high endemic rates or outbreaks?

Recommendation

1. Stratify data by patient location to target control measures when CDI incidence is above national and/or facility reduction goals or if an outbreak is noted (weak recommendation, low quality of evidence).

Strain Types and Changing Epidemiology

The emergence of the virulent, epidemic ribotype 027 strain was associated with increased incidence, severity, and mortality during the mid-2000s and resulted in outbreaks across North America [36, 48, 49], England [50, 51], parts of continental Europe [52, 53], and Asia [54]. The recent isolates of the 027 strain are more highly resistant to fluoroquinolones compared to historic strains of the same type [48]. This, coupled with increasing use of the fluoroquinolones worldwide likely promoted dissemination of a once uncommon strain [48].

Continued molecular typing will enable detection of emerging C. difficile strains with novel virulence factors, risk factors, and antibiotic resistance patterns. For example, evidence of emergence of a virulent strain, ribotype 078, has been reported from the Netherlands [57]. The prevalence of ribotype 078 increased between 2005 and 2008 and was associated with similar severity compared to CDI cases due to ribotype 027, but was associated with a younger population and more CA CDI. There was also a high degree of genetic relatedness between 078 isolates found in humans and pigs, an association also noted in the United States [58].

CDI in the Community and Special Populations and Increased Risk

In the context of the changing epidemiology of CDI in hospitals in the mid-2000s, evidence suggested increasing incidence of CDI in the community, even in healthy people previously at low risk, including peripartum women [59–64]. The sources of and risk factors for CA CDI (ie, occurring in patients with no inpatient stay in the previous 12 weeks) are not well defined. An analysis of CA CDI cases identified during 2009–2011 in the CDC EIP surveillance found that the majority of cases (82%) had some kind of healthcare exposure in the 12 weeks prior to CDI diagnosis. A relatively large percentage (36%) of CA CDI cases did not report antibiotic exposure in the 12 weeks prior to infection, although medication exposures were self-reported and may have been subject to limitations in recall. Among patients without reported antibiotic exposure, 31% received proton pump inhibitors (PPIs) [27]. In another recent study, a predictive risk scoring system developed in one cohort in a capitated-payment healthcare system and validated in another cohort in the same system proved useful for differentiating CDI risk in patients following an outpatient healthcare visit [65]. Major components of the scoring system included age, recent inpatient stay, chronic conditions (eg, liver and kidney disease, inflammatory bowel disease [IBD], cancer), and antibiotics; the role of PPIs was not examined or otherwise not included.

Patients with IBD, especially ulcerative colitis, are at increased risk of not only primary CDI but also recurrent disease, as well as increased morbidity and mortality from CDI. The risk of CDI within 5 years of a diagnosis of ulcerative colitis may be >3% and worsens prognosis by increasing risk of colectomy, postoperative complications, and death [66]. Patients with IBD are 33% more likely to suffer recurrent CDI [67]. There is an increased colectomy risk from CDI occurrence in patients with IBD overall, especially patients with ulcerative colitis [68].

Other patient populations at increased risk include solid organ transplant recipients: With an overall prevalence of 7.4%, rates in this population are 5-fold greater than among general medicine patients, and cases are associated with remarkable increases in hospital days and costs [69, 70]. Risks are highest in multiple solid organ transplants, followed by lung, liver, intestine, kidney, and pancreas with an overall prevalence of severe disease of 5.3% and risk of recurrence approximately 20% [70]. Patients with chronic kidney disease and end-stage renal disease have an approximately 2- to 2.5-fold increased risk of CDI and recurrence, a 1.5-fold increased risk of severe disease, and similarly increased mortality [71, 72]. Finally, hematopoietic stem cell transplant patients have a rate of CDI that is approximately 9 times greater than that in hospitalized patients overall; within this population, rates are about twice as high in allogeneic (vs autologous) transplants, where CDI occurs in about 1 in 10 transplants [73]. Most of this risk is during the peritransplantation period (ie, first 100 days posttransplant).

Epidemiology of Colonization and Infection

C. difficile transmission resulting in disease in the healthcare setting is most likely a result of person-to-person spread through the fecal–oral route or, alternatively, direct exposure to the contaminated environment. Studies have found that the prevalence of asymptomatic colonization with C. difficile is 3%–26% among adult inpatients in acute care hospitals [46, 74, 75] and is 5%–7% among elderly patients in LTCFs [33, 76]. In contrast, the prevalence of C. difficile in the stool among asymptomatic adults without recent healthcare facility exposure is <2% [77, 78]. A recent meta-analysis found that the pooled colonization rate upon hospital admission across 19 studies (mostly since 2005 and through 2014) was 8.1% with the main risk factor for such colonization being a previous hospitalization [79]. Notably, neither antibiotic use nor previous CDI was associated with colonization on hospital admission

The period between initial colonization with C. difficile and the occurrence of CDI (ie, incubation period) was estimated in 3 earlier studies to be a median of 2–3 days [66, 68]. However, recent evidence suggests a longer incubation period, even >1 week; Curry et al, in a study of asymptomatic C. difficile carriers, found 7 of 100 patients with CDI that tested positive for highly related C. difficile isolates 8–28 days prior to infection diagnosis [75]. Other early studies suggested that persons who remain asymptomatically colonized with C. difficile over longer periods of time are at decreased, rather than increased, risk for development of CDI [74, 80–82]. In contrast, the aforementioned recent meta-analysis found that preceding colonization increased the risk of subsequent CDI 6-fold; however, neither the time course from first detection of colonization to symptom onset nor the impact of diagnostic methods on this risk were examined [79].

Thus it is likely that the daily risk of progression from colonization to infection is not static but decreases over time; if so, the protection afforded by more long-standing colonization may be mediated in part by the boosting of serum antibody levels against C. difficile toxins A and B [46, 80, 81]. It is also likely that as long as an individual is colonized by one strain they are protected from infection caused by another strain; there is evidence of protection from CDI in both humans and in animal models following colonization with nontoxigenic strains, suggesting competition for nutrients or access to the mucosal surface [82, 83].

Routes of Transmission

The hands of healthcare personnel, transiently contaminated with C. difficile spores [84], and environmental contamination [75, 85–88] are probably the main means by which the organism is spread within healthcare. Although occupying a room where a prior occupant had CDI is a significant risk factor for CDI acquisition, this accounts for approximately 10% of CDI cases, indicating other vectors are more common [89]. There have also been outbreaks in which particular high-risk fomites, such as electronic rectal thermometers or inadequately cleaned commodes or bedpans, were shared between patients and were found to contribute to transmission [90].

The potential role of asymptomatically colonized patients in transmission has recently been highlighted. Using multilocus variable number of tandem repeats analysis, Curry et al found that 29% of CDI cases in a hospital were associated with asymptomatic carriers, compared to 30% that were associated with CDI patients [75]. Similarly, 2 studies of hospitalized patients in the United Kingdom found that only 25%–35% of CDI cases were genetically linked to previous CDI cases [91, 92], suggesting a role for other sources of transmission such as asymptomatic carriers and the environment. In the Curry et al study, environmental transmission may have occurred in 4 of 61 incident healthcare-associated CDI cases [75].

Two recent studies highlight how antibiotics may affect CDI risk in hospitalized patients through impacting the contagiousness of asymptomatically colonized patients. Through use of a multilevel model, ward-level antibiotic prescribing (ie, among both CDI and non-CDI patients, therefore including potential asymptomatic carriers) was found to be a risk factor for CDI that was independent of the risk from antibiotics and other factors in individual patients [93]. Meanwhile, the individual risk of symptomatic CDI was found to be higher in patients admitted to a room where a previous patient without CDI was administered antibiotics, suggesting induced shedding of C. difficile from asymptomatic carriers [94].

Shedding of C. difficile spores is particularly high among patients recently treated for CDI, even after resolution of diarrhea [84, 95], suggesting a population of asymptomatic carriers who might be more likely to transmit the organism. In one study, the frequency of skin contamination and environmental shedding remained high at the time of resolution of diarrhea (60% and 37%, respectively), decreased at the end of treatment, and increased again 1–4 weeks after treatment (58% and 50%, respectively) [95].

Risk Factors for Disease

Advanced age, potentially as a surrogate for severity of illness and comorbidities, is one of the most important risk factors for CDI [46, 96, 97], as is duration of hospitalization. The daily increase in the risk of C. difficile acquisition during hospitalization suggests that duration of hospitalization may be a proxy for the duration and degree of exposure to the organism, likelihood of exposure to antibiotics, and severity of underlying illness [46, 74, 98]. The most important modifiable risk factor for the development of CDI is exposure to antibiotic agents. Virtually every antibiotic has been associated with CDI through the years, but certain classes—third-/fourth-generation cephalosporins [99], fluoroquinolones [36, 37, 100], carbapenems [99], and clindamycin [101, 102]—have been found to be high risk. Receipt of antibiotics increases the risk of CDI because it suppresses the normal bowel microbiota, thereby providing a “niche” for C. difficile to flourish [103]. The relative risk of therapy with a given antibiotic agent and its association with CDI depends on the local prevalence of strains that are highly resistant to that particular antibiotic agent [101].

The disruption of the intestinal microbiota by antibiotics is long-lasting, and risk of CDI increases both during therapy and in the 3-month period following cessation of therapy. The highest risk of CDI (7- to 10-fold increase) appears to be during and in the first month after antibiotic exposure [99]. Both longer exposure to antibiotics [100] and exposure to multiple antibiotics increase the risk for CDI [100]. Nonetheless, even very limited exposure, such as single-dose surgical antibiotic prophylaxis, increases a patient’s risk of C. difficile colonization and symptomatic disease [104]. However, as previously noted, asymptomatic colonization, at least as detected among patients commonly admitted to the hospital, may not be associated with prior antibiotics [79].

Cancer chemotherapy is another risk factor for CDI that is, at least in part, mediated by the antibiotic activity of several chemotherapeutic agents [105, 106] but could also be related to the immunosuppressive effects of neutropenia [107, 108]. Evidence suggests that C. difficile is an important pathogen causing bacterial diarrhea in US patients infected with human immunodeficiency virus, which suggests that these patients are at specific increased risk because of their underlying immunosuppression, exposure to antibiotics, exposure to healthcare settings, or some combination of those factors [109]. Other risk factors for CDI include gastrointestinal surgery [102] or manipulation of the gastrointestinal tract, including tube feeding [110]. Meta-analyses of risk factors for recurrence identified many of those described above for initial CDI including advanced age, antibiotics during follow-up, PPIs, and strain type, as well previous exposure to fluoroquinolones [111, 112]. Meanwhile, risk factors for complicated disease include older age, leukocytosis, renal failure and comorbidities, while risk factors for mortality from CDI alone include age, comorbidities, hypoalbuminemia, leukocytosis, acute renal failure, and infection with ribotype 027 [112]. Recent data confirm the role of humoral immunity, primarily directed against toxin B, at least for protecting against recurrent disease [113]. There may be an important role for vitamin D in protecting against CDI, with low levels being an independent risk factor among both general patients with community-associated disease, older patients, and those with underlying inflammatory bowel disease [114, 115].

Breaches in the protective effect of stomach acid or the antibiotic activity of acid-suppressing medications, such as histamine-2 blockers and PPIs, while a potential risk factor, remain controversial. Although a number of studies have suggested an epidemiologic association between use of stomach acid–suppressing medications, primarily PPIs, and CDI [37, 60, 116–119], results of other well-controlled studies suggest this association is the result of confounding with the underlying severity of illness, non-CDI diarrhea, and duration of hospital stay [36, 120, 121].

In a retrospective study of 754 patients with healthcare-associated CDI, continuous use of PPIs was independently associated with a 50% increased risk for recurrence, whereas reexposure to antibiotics was associated with only a 30% increased risk [122]. Moreover, long-term use of PPIs has been shown to decrease lower gastrointestinal microbial diversity [123]. However, whether as a risk factor for primary or recurrent disease, the choice of control group in such epidemiologic studies is important. PPIs and histamine-2 blockers may be associated with CDI when comparing cases to nontested controls but not when comparing cases to tested-negative controls [120]. This reflects why understanding the role of these drugs in the pathogenesis of CDI remains elusive; PPIs induce diarrhea on their own, making it more likely patients are tested for CDI. More careful assessment of confounding factors, symptoms, and criteria for testing for recurrence, as is typical in a prospective clinical trial, may then explain why PPIs were not associated with recurrence in clinical trials of fidaxomicin [121].

Summary of Findings

Rationale

Summary of the Evidence

Surveillance

A recommended case definition for surveillance requires (1) the presence of diarrhea or evidence of megacolon or severe ileus and (2) either a positive laboratory diagnostic test result or evidence of pseudomembranes demonstrated by endoscopy or histopathology. An incident case is defined as a new primary episode of symptom onset (ie, no episode of symptom onset with positive result within the previous 8 weeks) and positive assay result (eg, toxin enzyme immunoassay [EIA] or nucleic acid amplification test [NAAT]). A recurrent case is defined as an episode of symptom onset and positive assay result following an episode with positive assay result in the previous 2–8 weeks. The minimum surveillance that should be performed by all healthcare facilities is tracking of healthcare facility–onset (HO) cases, which will allow for detection of elevated rates or an outbreak within the facility [15]. HO-CDI cases are defined by the Centers for Disease Control and Prevention (CDC)’s National Healthcare Safety Network (NHSN) as Laboratory-Identified (LabID) Events collected >3 days after admission to the facility (ie, on or after day 4) [16]. Facilities may also monitor cases of CDI occurring within 28 days after discharge from a healthcare facility, which are considered community-onset, healthcare facility-associated (CO-HCFA) cases (ie, postdischarge cases).

Because the risk of CDI increases with the length of stay, the most appropriate denominator for HO-CDI rates is the number of patient-days. If a facility notes an increase in the incidence of CDI from the baseline rate, or if the incidence is higher than in comparable institutions or above national and/or facility reduction goals, surveillance data should be stratified by hospital location or clinical service to identify particular patient populations where infection prevention measures may be targeted. In addition, measures should be considered for tracking severe outcomes, such as colectomy, intensive care unit (ICU) admission, or death, attributable to CDI.

In the United States, CDI surveillance in healthcare facilities is conducted via the CDC’s NHSN Multidrug-Resistant Organism and C. difficile Infection Module LabID Event Reporting [16]. To allow for risk-adjusted reporting of healthcare-associated infections (HAIs), CDC calculates the standardized infection ratio (SIR) by dividing the number of observed events by the number of predicted events. The number of predicted events is calculated using LabID probabilities estimated from models constructed from NHSN data during a baseline time period, which represents a standard population [16]. These have been recently updated using a 2015 baseline period with specific models developed for each of 4 facility types: acute care hospitals, long-term acute care hospitals, critical access hospitals (rural hospitals with ≤25 acute care inpatient beds), and inpatient rehabilitation facilities [17]. Use of more sensitive tests (eg, NAATs) for C. difficile have been demonstrated to result in substantial increases in reported CDI incidence rates compared with those derived from toxin detection by enzyme immunoassay [18, 19]. Consistent with this, the impact of test type on facilities’ reported rates is an independent predictor in each of the aforementioned NHSN risk adjustment models except that for critical access hospitals [17]. The prevalence of CO cases not associated with the facility (ie, defined in NHSN as present-on-admission with no discharge from the same facility within the previous 4 weeks) is also associated with HO-CDI [20, 21]. This likely reflects colonization pressure in the admitted patient population, and is an independent predictor in each of the NHSN risk adjustment models except for inpatient rehabilitation facilities [17].

Despite these attempts to risk-adjust based upon data that hospitals are already reporting to NHSN, there are limitations. For example, adjustment by test type accounts for only the pooled mean impact on rates resulting from differences in sensitivity between major test categories (eg, NAAT, toxin EIA) and does not account for differences in sensitivity between individual test manufacturers, nor potential interaction of C. difficile strain types on relative test sensitivity [22, 23]. Similarly, there are inherent limitations in all surveillance adjusting for the disease risk in the surveyed population. For example, Thompson et al demonstrated how the Medicare Case Mix Index, a summary metric calculated at the hospital level and reflecting clinical complexity and resource consumption of patients within a hospital, could further explain variation across hospital CDI rates over and above the existing model [24]. However, any potential benefit to hospital performance improvement from additional risk adjustment strategies must be balanced by any increased data-reporting burden or impact on timeliness.

Prevalence, Incidence, Morbidity, and Mortality

C. difficile is the most commonly recognized cause of infectious diarrhea in healthcare settings. Among 711 acute care hospitals in 28 states conducting facility-wide inpatient LabID-CDI event reporting to NHSN in 2010, the pooled rate of HO-CDI was 7.4 (median, 5.4) per 10000 patient-days [25]. As these data were reported prior to development of the SIR, they were unadjusted; at that time, 35% of NHSN hospitals reported using NAATs. Based on data from the CDC’s Emerging Infections Program (EIP) [26] population-based surveillance system in 2011, the estimated number of incident CDI cases in the United States was 453000 (95% confidence interval [CI], 397100–508 500), with an incidence of 147.2 (95% CI, 129.1–165.3) cases/100000 persons [6]. The incidence was highest among those aged ≥65 years (627.7) and was greater among females and whites. Of the total estimated 453000 incident cases, 293300 (64.7%) were considered to be healthcare-associated, of which 37% were HO, 36% had their onset in long-term care facilities (LTCFs), and 28% were CO healthcare-associated (ie, specimen collected in an outpatient setting or ≤3 calendar days after hospital admission and documented overnight stay in a healthcare facility in the prior 12 weeks). Of the estimated 159700 community-associated CDI cases (ie, no documented overnight stay in a healthcare facility in the prior 12 weeks), 82% were associated with outpatient healthcare exposure; therefore, the overwhelming majority (94%) of all cases of CDI had a recent healthcare exposure [6, 27].

A multistate prevalence survey of HAIs conducted by EIP in 2011 found that C. difficile was the most common causative pathogen, accounting for 61 of 504 (12.1%) HAIs identified in 183 hospitals [28]. The increasing burden of CDI was also noted in a network of community hospitals in the southeastern United States, where C. difficile surpassed methicillin-resistant Staphylococcus aureus (MRSA) as the most common cause of HAIs [29].

Recent hospital discharge data [30] indicate that the total number of hospital discharges with a diagnosis of CDI in the United States plateaued at historic highs between 2011 and 2013. During this apparent plateau in hospital discharges, there has been an 8% decline in the risk-adjusted HO-CDI SIR of NHSN [31].

As most LTCFs do not report CDI data, limited data are available about the burden of CDI in these settings. LTCF residents are often elderly, have numerous comorbid conditions, and have been exposed to antibiotics, which are important risk factors for C. difficile colonization and infection [32, 33]. Data from the CDC EIP and other sources suggest that the burden is high; >20% of all CDIs identified in 2011 had onset in LTCFs [6]. Furthermore, in 2012 there were an estimated 112800 cases of CDI with onset in LTCFs [34]; 57% of these patients were discharged from a hospital within 1 month. Conversely, 20% of HO-CDI cases were found to occur in patients who had been LTCF residents any time in the previous 12 weeks [5]. Using a multilevel longitudinal nested case-control study of Veterans Affairs LTCFs, all but 25% of the variability in LTCF rates could be explained by 2 factors: the importation of active or convalescing cases with hospital-onset CDI in the previous 8 weeks, and LTCF antibiotic use as measured by antibiotic days per 10000 resident-days [35].

Severity of CDI has been reported to have increased coincident with the increasing incidence during the outbreaks and emergence of the PCR ribotype 027 epidemic strain (also known as the North American pulsed field type 1 [NAP1] or restriction endonuclease analysis pattern “BI”) in the 2000s [36, 37]. Severity of CDI has been variably defined based on laboratory data, physical examination findings, ICU stay, colectomy, and/or mortality. Reported colectomy rates in hospitalized patients with CDI during endemic periods range from 0.3% to 1.3%, whereas during epidemic periods, colectomy rates range from 1.8% to 6.2% [38]. Other indicators of CDI morbidity include recurrent CDI, readmissions to the hospital, and discharge to LTCFs. Overall, 0.8% of patients develop candidemia in the 120 days after CDI and both more severe CDI and treatment with the combination of vancomycin and metronidazole are associated with increased candidemia risk [39]. After a first diagnosis of CDI, 10%–30% of patients develop at least 1 recurrent CDI episode, and the risk of recurrence increases with each successive recurrence [40, 41]. A national estimate of first CDI recurrences in 2011 was 83000 (95% CI, 57100–108900) [6].

Recommendation

Diagnosis (Pediatric Considerations)

XI. When should a neonate or infant be tested for C. difficile?

Recommendations

1. Because of the high prevalence of asymptomatic carriage of toxigenic C. difficile in infants, testing for CDI should never be routinely recommended for neonates or infants ≤12 months of age with diarrhea (strong recommendation, moderate quality of evidence).

Summary of the Evidence

The rate of C. difficile colonization among asymptomatic infants can exceed 40% [136, 143, 154]. Colonization rates among hospitalized neonates are greater than observed for healthy infants [136]. Although the rate of colonization declines over the first year of life, intermittent detection of C. difficile toxin can persist throughout infancy [202]. C. difficile toxin can still be detected in approximately 15% of 12-month-old infants [153]. Thus, there is a substantial risk of a biologic false positive when C. difficile diagnostic testing is performed in neonates and infants. Another challenge to defining when an infant with diarrhea should be tested for C. difficile is the absence of a validated definition of clinically significant diarrhea in this age group, where passage of frequent loose stools is common. Children <12 months of age should only be tested for C. difficile if they have evidence of pseudomembranous colitis or toxic megacolon, or if they have clinically significant diarrhea and other causes of diarrhea have been excluded.

XII. When should a toddler or older child be tested for C. difficile?

Recommendations

1. C. difficile testing should not be routinely performed in children with diarrhea who are 1–2 years of age unless other infectious or noninfectious causes have been excluded (weak recommendation, low quality of evidence).
2. In children ≥2 years of age, C. difficile testing is recommended for patients with prolonged or worsening diarrhea and risk factors (eg, underlying inflammatory bowel disease or immunocompromising conditions) or relevant exposures (eg, contact with the healthcare system or recent antibiotics) (weak recommendation, moderate quality of evidence).

Summary of the Evidence

The prevalence of asymptomatic colonization with C. difficile is elevated in the second year of life, although to a lesser degree than in infants [139, 153, 154]. Therefore, testing in this population should also be avoided unless other infectious and noninfectious causes of diarrhea have been excluded. However, by 2–3 years of age, approximately 1%–3% of children are asymptomatic carriers of C. difficile (a rate similar to that observed in healthy adults). Rarely, some conditions such as Hirschprung disease may predispose young children to CDI, and testing should be considered in this population [203, 204]. The role of C. difficile in community-onset diarrhea in otherwise healthy young children remains controversial. Studies of children hospitalized with acute gastroenteritis have documented that C. difficile can be isolated in >50% of children in whom an alternate gastrointestinal pathogen has been identified [205]. Additionally, one recently published study found that among 100 children <2 years of age who were hospitalized with diarrhea and had C. difficile toxin detected; all had resolution of diarrhea regardless of whether C. difficile–specific therapy was administered [206]. Limited data suggest that identification of multiple enteric pathogens (including C. difficile) may predict more severe symptoms [205].

Infection Prevention and Control: Isolation Measures for Patients with CDI

XIII. Should private rooms and/or dedicated toilet facilities be used for isolated patients with CDI?

Recommendations

1. Accommodate patients with CDI in a private room with a dedicated toilet to decrease transmission to other patients. If there is a limited number of private single rooms, prioritize patients with stool incontinence for placement in private rooms (strong recommendation, moderate quality of evidence).
2. If cohorting is required, it is recommended to cohort patients infected or colonized with the same organism(s)—that is, do not cohort patients with CDI who are discordant for other multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus (strong recommendation, moderate quality of evidence).

Summary of the Evidence

Isolation of patients with CDI or suspected CDI is a prevention measure used by most healthcare facilities regardless of local epidemiology; however, additional measures are often implemented, particularly when CDI rates are high. An infection control “bundle” strategy has been used to successfully control major CDI outbreaks [207–211]. The “bundle” approach involves multifaceted interventions and includes hand hygiene, isolation measures, environmental disinfection, and antibiotic stewardship. However, it is often difficult to determine which interventions were the most effective in controlling the outbreak as they are implemented simultaneously.

Hospital room design and handwashing accessibility are essential elements in the prevention and control of CDI. Private rooms may facilitate better infection control practices. In a cohort study of healthcare-associated CDI acquisition, higher rates of CDI were demonstrated among patients housed in double rooms than in single rooms (17% vs 7%; P = .08) and there was a significantly higher risk of acquisition after exposure to a roommate with a positive culture result [74]. The effect of private rooms on CDI and other bacterial acquisition rates was studied when an ICU was renovated to only private rooms with accessible handwashing facilities [212]. There was a significant reduction in CDI rates by 43%, although other potential confounders, such as antibiotic utilization, were not examined [212]. Private rooms may not be available and cohorting patients with CDI in a multibed room may be required. The risk of recurrence was examined among patients with CDI admitted to a cohort ward while adjusted for potential risk factors such as age, comorbidities, and continued antibiotic use [213]. Admission to a C. difficile cohort ward was shown to be an independent predictor for recurrence [213]. If cohorting is required, dedicated commodes should be provided to the patients to reduce further cross-transmission.

In conclusion, patients with CDI should be placed in a private room to decrease transmission to other patients. If there is a limited number of private single rooms, CDI patients with stool incontinence should be prioritized for placement in private rooms. If cohorting is required, it is recommended to cohort patients infected or colonized with the same organism(s) ie, do not cohort patients with CDI who are discordant for other multidrug-resistant organisms such as MRSA or vancomycin-resistant Enterococcus (VRE).

XIV. Should gloves and gowns be worn while caring for isolated CDI patients?

Recommendation

1. Healthcare personnel must use gloves (strong recommendation, high quality of evidence) and gowns (strong recommendation, moderate quality of evidence) on entry to a room of a patient with CDI and while caring for patients with CDI.

Summary of the Evidence

Additional isolation techniques (contact precautions, private rooms, and cohorting of patients with active CDI) have been used for control of outbreaks, with variable success [207, 214, 215]. Contact precautions include the donning of gowns and gloves when caring for patients with CDI. The hands of personnel can become contaminated with C. difficile spores, particularly when gloves are not used and when exposed to fecal soiling [74, 216]. Wearing gloves in conjunction with hand hygiene should decrease the concentration of C. difficile organisms on the hands of healthcare personnel. A prospective controlled trial of vinyl glove use for handling body substances showed a significant decrease in CDI rates, from 7.7 cases per 1000 discharges before institution of glove use to 1.5 cases per 1000 discharges after institution of glove use (P=.015), but not on control wards that did not institute the glove intervention [217]. Care should also be taken to prevent contamination of hands when removing gloves.

C. difficile has been detected on nursing uniforms, but there is no evidence that uniforms are a source of transmission to patients [218]. The use of gowns has been recommended because of potential soiling and contamination of the uniforms of healthcare personnel with C. difficile and high quality of evidence for reducing transmission of other enteric multidrug-resistant organisms (ie, VRE) [219, 220]. In addition, the fact that gloves reduce transmission provides further indirect evidence for gowns.

XV. When should isolation be implemented?

Recommendation

1. Patients with suspected CDI should be placed on preemptive contact precautions pending the C. difficile test results if test results cannot be obtained on the same day (strong recommendation, moderate quality of evidence).

Summary of the Evidence

It is important to place patients suspected of having CDI on contact precautions before diagnostic laboratory test confirmation if there will be a lag before test results are available. In a prospective study of 100 patients suspected of CDI, skin contamination was evaluated as well as the average time for test results to become available [221]. The potential for healthcare personnel hand contamination was assessed by applying sterile gloved hands to frequently examined patient skin sites and then imprinting the gloves onto agar for C. difficile culture. Twenty of these 100 patients (20%) were diagnosed with CDI but the test results were not available for 2.07 days. The frequency of C. difficile acquisition on gloved hands of healthcare personnel after skin contact with these patients was 69%. This study supports that patients with suspected CDI should be placed on preemptive contact precautions pending the C. difficile test results if the results cannot be obtained the same day as when the specimen was collected.

XVI. How long should isolation be continued?

Summary of Findings

Recommendation

The EORTC/MSG revised criteria for defining IFIs, including IA, require a microbiologic and/or histopathologic diagnosis to define proven infection [64]. However, specimen acquisition is challenging in many patients. Histopathologic evidence of fungi is crucial to determine the significance of Aspergillus growing in culture, yet diagnostic accuracy of histopathology is suboptimal [65–67]. Moreover, these methods are time-consuming and insensitive. The most common specimens obtained are lung tissue by transthoracic percutaneous needle aspiration or video-assisted thoracoscopic biopsy, and bronchial lavage/wash specimens. These specimens should be submitted in adequate quantities for both histopathologic/cytologic testing and culture with a brief clinical history to aid the pathologist and microbiologist in interpretation of findings [68–72]. Methods to optimize yield should be employed including adequate quantity of specimens, timely delivery of fresh specimen to the laboratory or refrigeration if delay is anticipated (although refrigeration may reduce the recovery of some organisms, eg, Mucorales), incubation of cultures for at least 5 days (and up to 3 weeks for other fungal pathogens), and communication of suspicion for fungal infection with pathology and microbiology laboratory personnel [73]. In the pathology laboratory, standard and special fungal stains on fluid or tissue should be performed simultaneously when a fungal infection is suspected and may reveal the characteristic acute angle branching septate hyphae of Aspergillus spp. Molecular assays targeting ribosomal DNA sequences can also be used for detection of Aspergillus in tissues, although these methods have not been standardized nor cleared by the US Food and Drug Administration (FDA) for clinical use. The optical brightener methods, Calcofluor or Blankophor, are rapid stains utilized for direct examination and have a high sensitivity and specificity for detecting Aspergillus-like features [74, 75]. 

Results

Since the last IDSA guidelines, there have been numerous publications assessing the performance of Aspergillus PCR in clinical samples. Overall, direct comparison studies have shown Aspergillus PCR to be substantially more sensitive than culture in blood and respiratory fluids. In a meta-analysis of clinical trials evaluating the accuracy of serum or whole-blood PCR assays for IA, sensitivity and specificity were 84% and 76%, respectively [77]. These values are promising, but PCR of blood or serum is unable on its own to confirm or exclude suspected IA in high-risk patients. The sensitivity of Aspergillus PCR on BAL fluid was higher than within blood, but in many instances its specificity was lower [78, 79]. In a systematic review of 9 studies using reference IA definitions strictly adherent to the EORTC/MSG criteria, the sensitivity and specificity of PCR of BAL were 77% and 94%, respectively [78]. Data included large 95% confidence intervals (CIs) that were attributed to the use of different PCR assays and inclusion of heterogeneous patient populations [78, 79]. The lower specificity in BAL has been attributed to the fact that lungs are often colonized by Aspergillus (particularly in many high-risk populations, such as lung transplant recipients), and that PCR is not able to differentiate colonization from disease or to distinguish different Aspergillus spp. The high negative predictive value of BAL PCR (usually ≥95%) suggests a role in ruling out IPA. 

Summary of Findings

Notes

Acknowledgments

The expert panel expresses its gratitude for thoughtful reviews of an earlier version by Curtis Collins, PharmD of the ASHP, Christopher Ohl, MD, and Ellie Goldstein, MD. The panel greatly appreciates National Jewish Health for assistance with the literature searches and Valery Lavergne, MD, Paul Alexander, PhD, and Genet Demisashi of the IDSA for their assistance and support in the development of these guidelines.

Disclaimer

The findings and conclusions in this report are those of the author(s), and do not necessarily represent the official position of the CDC or the US Department of Veterans Affairs.

Financial support

Support for this guideline was provided by the IDSA and SHEA.

Potential Conflicts of Interest

The following list is a reflection of what has been reported to IDSA. To provide thorough transparency, IDSA requires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conflicts of interest (COI) is determined by a review process that includes assessment by the Standards and Practice Guidelines Committee (SPGC) Chair, the SPGC liaison to the development Panel, the Board of Directors liaison to the SPGC, and, if necessary, the COI Task Force of the Board. This assessment of disclosed relationships for possible COI will be based on the relative weight of the financial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. For activities outside of the submitted work, D. G. has served as board member for Rebiotix, Merck, Actelion, Summit, and DaVolterra; has served as a consultant for Pfizer, Sanofi Pasteur, and MGB Pharma; received a grant from Seres Therapeutics; and holds patents and technology for nontoxigenic C. difficile for the treatment and prevention of CDI under NTCD, LLC. For activities outside of the submitted work, S. J. has served on the advisory board member for Bio-k+, Synthetic Biologics, Summit, Therapeutics, and CutisPharma; has served on Pfizer’s data and safety monitoring board for vaccine study; and has received payment for lectures from Merck. For activities outside of the submitted work, K. C. has received research grants from GenePOC, Accelerate, and BD Diagnostics; has received royalties from McGraw-Hill and ASM Press; and has received travel expenses as board member with ASM. For activities outside of the submitted work, S. C. has received payment as expert testimony for medical-legal consultation; has received research grants from the Agency for Health Research and Quality, CDC, and National Institutes of Health (NIH); and has received payment for lectures from IDSA, CDC, and American Academy of Pediatrics. For activities outside of the submitted work, E. R. D. has served as a consultant for Sanofi Pasteur, Nestle, Valneva, Pfizer, Rebiotix, GSK, and Merck; has received research grants from Sanofi Pasteur, Pfizer, Merck, and Rebiotix; and has received payment for lectures from Alere and Biofire. For activities outside of the submitted work, K. G. has received research grants from Merck & Co, Summit Pharmaceuticals, and Techlab, served as a consultant for bioMérieux, Merck & Co, and Summit Pharmaceuticals; and received payment for the development of educational presentation by bioMérieux and Merck & Co. For activities outside of the submitted work, C. K. has received research grants from the NIH, Institut Mérieux, and Aptalis; has received personal fees serving as scientific advisor for Facile Therapeutics, Summit (Oxford), Synthetic Biologics, Actelion, Artugen, First Light Diagnostics, Finch, GlaxoSmithKline, Merck, Seres Therapeutics, Summit, Vedanta, Celimmune, Cour Pharma, Takeda, Innovate, Valeant, and ImmunogenX; and has received payment for the development of educational presentations by Merck and Seres. For activities outside of the submitted work, V. L. has served as a consultant for Merck, and received payment for serving on the speaker’s bureau for Merck. For activities outside of the submitted work, J. S. has received grants from CDC Epicenters. For activities outside of the submitted work, M. W. has received research grants, consultancy/lecture fees from Actelion, Cubist, Astellas, Optimer, Sanofi Pasteur, Summit, Seres, bioMérieux, Da Volterra, Qiagen, and Pfizer; served as a consultant for Merck, Valneva, Alere, AstraZeneca, Durata, Nabriva, Pfizer, Roche, The Medicines Company, Abott, Basilea, and the European Tissue Symposium; and received research grants from Cerexa, Abbott, and the European Tissue Symposium. All other authors report no potential conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA and SHEA consider adherence to the guidelines listed below to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s individual circumstances. While IDSA makes every effort to present accurate and reliable information, the information provided in these guidelines is “as is” without any warranty of accuracy, reliability, or otherwise, either express or implied. Neither IDSA nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented.

Update History

This is an update, now using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology, of the 2008 Infectious Diseases Society of America and Society (IDSA) and Society of Critical Care Medicine (SCCM) guideline for the evaluation of new-onset fever in adult ICU patients without severe immunocompromise (3). Any recommendation from the 2008 guideline not specifically addressed in this update remains in place. In this document, we address microbiologic studies, imaging procedures, and the use of biomarkers in the diagnostic evaluation of fever with initial onset after ICU admission, focusing on detection of potential infectious etiologies. It should be noted that not all febrile episodes dictate a need for investigation, that is, those in which a noninfectious etiology is obvious such as fever occurring immediately in the postoperative state. For those fevers that do require investigation, a good history and physical examination will often reveal potential sources of infection. Diagnostic studies should then be sent with those potential sources in focus rather than reflexively sending cultures for all possible sources. Although much of this document and its recommendations may be applicable to severely immunocompromised patients, such as organ transplant recipients and those with severe neutropenia, these populations are not directly addressed here. The variability and complexities of different types of immunocompromise make this a task that cannot be accomplished in the context of a generally applicable guideline.

The guideline is intended for use by members of multidisciplinary care teams managing mixed populations of critically ill patients in the ICU, including intensivists, infectious diseases specialists, advanced practice providers, clinical pharmacists, nurses, respiratory therapists, and policymakers.